Acceleration of Photoinduced Electron Transfer by Modulating Electronegativity of Substituents in Stable Zr-Metal-Organic Frameworks to Boost Photocatalytic CO2 Reduction.

Photoreduction of CO2 with water into chemical feedstocks of fuels provides a green way to help solve both the energy crisis and carbon emission issues. Metal-organic frameworks (MOFs) show great potential for CO2 photoreduction. However, poor water stability and sluggish charge transfer could limit their application. Herein, three water-stable MOFs functionalized with electron-donating methyl groups and/or electron-withdrawing trifluoromethyl groups are obtained for the CO2 photoreduction. Compared with UiO-67-o-CF3-CH3 and UiO-67-o-(CF3)2, UiO-67-o-(CH3)2 achieves excellent performance with an average CO generation rate of 178.0 µmol g-1 h-1 without using any organic solvent or sacrificial reagent. The superior photocatalytic activity of UiO-67-o-(CH3)2 is attributed to the fact that compared with trifluoromethyl groups, methyl groups could not only elevate CO2 adsorption capacity and reduction potential but also promote photoinduced charge separation and migration. These are evidenced by gas physisorption, photoluminescence, time-resolved photoluminescence, electrochemical impedance spectroscopy, transient photocurrent characteristics, and density functional theory calculations. The possible working mechanisms of electron-donating methyl groups are also proposed. Moreover, UiO-67-o-(CH3)2 demonstrates excellent reusability for the CO2 reduction. Based on these results, it could be affirmed that the strategy of modulating substituent electronegativity could provide guidance for designing highly efficient photocatalysts.

Efficient Inhibition of Deep Conversion of Partial Oxidation Products in C-H Bonds' Functionalization Utilizing O2 via Relay Catalysis of Dual Metalloporphyrins on Surface of Hybrid Silica Possessing Capacity for Product Exclusion.

To inhibit the deep conversion of partial oxidation products (POX-products) in C-H bonds' functionalization utilizing O2, 5-(4-(chloromethyl)phenyl)-10,15,20-tris(perfluorophenyl)porphyrin cobalt(II) and 5-(4-(chloromethyl)phenyl)-10,15,20-tris(perfluorophenyl)porphyrin copper(II) were immobilized on the surface of hybrid silica to conduct relay catalysis on the surface. Fluorocarbons with low polarity and heterogeneous catalysis were devised to decrease the convenient accessibility of polar POX-products to catalytic centers on the lower polar surface. Relay catalysis between Co and Cu was designed to utilize the oxidation intermediates alkyl hydroperoxides to transform more C-H bonds. Systematic characterizations were conducted to investigate the structure of catalytic materials and confirm their successful syntheses. Applied to C-H bond oxidation, not only deep conversion of POX-products was inhibited but also substrate conversion and POX-product selectivity were improved simultaneously. For cyclohexane oxidation, conversion was improved from 3.87% to 5.27% with selectivity from 84.8% to 92.3%, which was mainly attributed to the relay catalysis on the surface excluding products. The effects of the catalytic materials, product exclusion, relay catalysis, kinetic study, substrate scope, and reaction mechanism were also investigated. To our knowledge, a practical and novel strategy was presented to inhibit the deep conversion of POX-products and to achieve efficient and accurate oxidative functionalization of hydrocarbons. Also, a valuable protocol was provided to avoid over-reaction in other chemical transformations requiring high selectivity.

Tri-enzyme fusion of tryptophan halogenase achieves a concise strategy for coenzyme self-sufficiency and the continuous halogenation of L-tryptophan.

The halogenase-based catalysis is one of the most environmentally friendly methods for the synthesis of halogenated products, among which flavin-dependent halogenases (FDHs) have attracted great interest as one of the most promising biocatalysts due to the remarkable site-selectivity and wide substrate range. However, the complexity of constructing the NAD+-NADH-FAD-FADH2 bicoenzyme cycle system has affected the engineering applications of FDHs. In this work, a coenzyme self-sufficient tri-enzyme fusion was constructed and successfully applied to the continuous halogenation of L-tryptophan. SpFDH was firstly identified derived from Streptomyces pratensis, a highly selective halogenase capable of generating 6-chloro-tryptophan from tryptophan. Then, using gene fusion technology, SpFDH was fused with glucose dehydrogenase (GDH) and flavin reductase (FR) to form a tri-enzyme fusion, which increased the yield by 1.46-fold and making the coenzymes self-sufficient. For more efficient halogenation of L-tryptophan, a continuous halogenation bioprocess of L-tryptophan was developed by immobilizing the tri-enzyme fusion and attaching it to a continuous catalytic device, which resulted in a reaction yield of 97.6% after 12 h reaction. An FDH from S. pratensis was successfully applied in the halogenation and our study provides a concise strategy for the preparation of halogenated tryptophan mediated by multienzyme cascade catalysis.

Gochujang, a traditional Korean fermented food, protects through suppressed inflammatory pathways and histological structure disruption in dextran sodium sulfate (DSS)-induced colitis mice.

The mechanisms underlying chronic inflammatory diseases remain unclear. Therefore, researchers have explored the mechanisms underlying colitis using diverse materials. Recently, there has been an increasing interest in fermented products and bioconversion materials, their potential efficacy is being actively studied. Gochujang, a traditional Korean fermented product, is crafted by blending fermented Meju powder, gochu (Korean chili) powder, glutinous rice, and salt. In our study, we explored the effectiveness of Gochujang (500 mg/kg; Cheongju and Hongcheon, Korea) in dextran sulfate sodium (DSS)-induced colitis mice model. Gochujang was orally administered for 2 weeks, followed by the induction of colitis using 3% DSS in the previous week. During our investigation, Gochujang variants (TCG22-25, Cheongju and TCG22-48, Hongcheon) did not exhibit significant inhibition of weight reduction (p = 0.061) but notably (p = 0.001) suppressed the reduction in large intestine length in DSS-induced colitis mice. In the serum from colitis mice, TCG22-48 demonstrated reduced levels of the inflammatory cytokines interleukin (IL)-6 (p = 0.001) and tumor necrosis factor (TNF)-α (p = 0.001). Additionally, it inhibited the phosphorylation of Erk (p = 0.028), p38, and NF-κB (p = 0.001) the inflammatory mechanism. In our study, TCG22-25 demonstrated a reduction in the IL-6 level (p = 0.001) in serum and inhibited the phosphorylation of p38 and NF-κB (p = 0.001). Histological analysis revealed a significant (p = 0.001) reduction in the pathological score of the large intestine from TCG22-25 and TCG22-48. In conclusion, the intake of Gochujang demonstrates potent anti-inflammatory effects, mitigating colitis by preventing the large intestine length reduction of animals with colitis, lowering serum levels of TNF-α and IL-6 cytokines, and inhibiting histological disruption and inflammatory mechanism phosphorylation.

Working memory components modulation of attentional disengagement from evaluative distractor.

It is important for people to disengage attention from a distraction, which can help them complete the task at hand as quickly as possible. Recent studies have shown that people's attention stays longer on reward-distractors than on loss-distractors, and a delay in attentional disengagement is noted when reward-distractors are present. However, few studies have examined whether attentional disengagement from an evaluative distractor relies upon working memory (WM) components. In the present study, we used an attentional disengagement paradigm in which reward- or loss-distractors were presented at a central location and the target was presented at a peripheral location, in combination with different WM tasks. The results from Experiment 1 showed that participants were slower to disengage their attention from a central reward-distractor than a loss-distractor regardless of cognitive load when the phonological loop component of WM was involved. The results from Experiment 2 revealed that people had difficulty in shifting their attention away from a reward-distractor in comparison to a loss-distractor when spatial WM was low, whereas no such difference was observed when spatial WM was high. We conclude that WM components differently modulate attentional disengagement from evaluative distractors. That is, the processing of evaluative (reward and loss) distractors may rely on the same cognitive resources as the spatial WM component, but not the phonological loop component.

Nitrogen-Rich Conjugated Microporous Polymers with Improved Cobalt(II) Density for Highly Efficient Electrocatalytic Oxygen Evolution.

Developing efficient oxygen evolution catalysts (OECs) made from earth-abundant elements is extremely important since the oxygen evolution reaction (OER) with sluggish kinetics hinders the development of many energy-related electrochemical devices. Herein, an efficient strategy is developed to prepare conjugated microporous polymers (CMPs) with abundant and uniform coordination sites by coupling the N-rich organic monomer 2,4,6-tris(5-bromopyrimidin-2-yl)-1,3,5-triazine (TBPT) with Co(II) porphyrin. The resulting CMP-Py(Co) is further metallized with Co2+ ions to obtain CMP-Py(Co)@Co. Structural characterization results reveal that CMP-Py(Co)@Co has higher Co2+ content (12.20 wt %) and affinity toward water compared with CMP-Py(Co). Moreover, CMP-Py(Co)@Co exhibits an excellent OER activity with a low overpotential of 285 mV vs RHE at 10 mA cm-2 and a Tafel slope of 80.1 mV dec-1, which are significantly lower than those of CMP-Py(Co) (335 mV vs RHE and 96.8 mV dec-1). More interestingly, CMP-Py(Co)@Co outperforms most reported porous organic polymer-based OECs and the benchmark RuO2 catalyst (320 mV vs RHE and 87.6 mV dec-1). Additionally, Co2+-free CMP-Py(2H) has negligible OER activity. Thereby, the enhanced OER activity of CMP-Py(Co)@Co is attributed to the incorporation of Co2+ ions leading to rich active sites and enlarged electrochemical surface areas. Density functional theory (DFT) calculations reveal that Co2+-TBPT sites have higher activity than Co2+-porphyrin sites for the OER. These results indicate that the introduction of rich active metal sites in stable and conductive CMPs could provide novel guidance for designing efficient OECs.

Genome Assembly of Cordia subcordata, a Coastal Protection Species in Tropical Coral Islands.

Cordia subcordata trees or shrubs, belonging to the Boraginaceae family, have strong resistance and have adapted to their habitat on a tropical coral island in China, but the lack of genome information regarding its genetic background is unclear. In this study, the genome was assembled using both short/long whole genome sequencing reads and Hi-C reads. The assembled genome was 475.3 Mb, with 468.7 Mb (99.22%) of the sequences assembled into 16 chromosomes. Repeat sequences accounted for 54.41% of the assembled genome. A total of 26,615 genes were predicted, and 25,730 genes were functionally annotated using different annotation databases. Based on its genome and the other 17 species, phylogenetic analysis using 336 single-copy genes obtained from ortholog analysis showed that C. subcordata was a sister to Coffea eugenioides, and the divergence time was estimated to be 77 MYA between the two species. Gene family evolution analysis indicated that the significantly expanded gene families were functionally related to chemical defenses against diseases. These results can provide a reference to a deeper understanding of the genetic background of C. subcordata and can be helpful in exploring its adaptation mechanism on tropical coral islands in the future.

Bioinformatic and functional characterization of cyclic-di-GMP metabolic proteins in Vibrio alginolyticus unveils key diguanylate cyclases controlling multiple biofilm-associated phenotypes.

The biofilm lifestyle is critical for bacterial survival and proliferation in the fluctuating marine environment. Cyclic diguanylate (c-di-GMP) is a key second messenger during bacterial adaptation to various environmental signals, which has been identified as a master regulator of biofilm formation. However, little is known about whether and how c-di-GMP signaling regulates biofilm formation in Vibrio alginolyticus, a globally dominant marine pathogen. Here, a large set of 63 proteins were predicted to participate in c-di-GMP metabolism (biosynthesis or degradation) in a pathogenic V. alginolyticus strain HN08155. Guided by protein homology, conserved domains and gene context information, a representative subset of 22 c-di-GMP metabolic proteins were selected to determine which ones affect biofilm-associated phenotypes. By comparing phenotypic differences between the wild-type and mutants or overexpression strains, we found that 22 c-di-GMP metabolic proteins can separately regulate different phenotypic outputs in V. alginolyticus. The results indicated that overexpression of four c-di-GMP metabolic proteins, including VA0356, VA1591 (CdgM), VA4033 (DgcB) and VA0088, strongly enhanced rugose colony morphotypes and strengthened Congo Red (CR) binding capacity, both of which are indicators of biofilm matrix overproduction. Furthermore, rugose enhanced colonies were accompanied by increased transcript levels of extracellular polysaccharide (EPS) biosynthesis genes and decreased expression of flagellar synthesis genes compared to smooth colonies (WTpBAD control), as demonstrated by overexpression strains WTp4033 and ∆VA4033p4033. Overall, the high abundance of c-di-GMP metabolic proteins in V. alginolyticus suggests that c-di-GMP signaling and regulatory system could play a key role in its response and adaptation to the ever-changing marine environment. This work provides a robust foundation for the study of the molecular mechanisms of c-di-GMP in the biofilm formation of V. alginolyticus.

Different patterns of foreground and background processing contribute to texture segregation in humans: an electrophysiological study.

Background: Figure-ground segregation is a necessary process for accurate visual recognition. Previous neurophysiological and human brain imaging studies have suggested that foreground-background segregation relies on both enhanced foreground representation and suppressed background representation. However, in humans, it is not known when and how foreground and background processing play a role in texture segregation. Methods: To answer this question, it is crucial to extract and dissociate the neural signals elicited by the foreground and background of a figure texture with high temporal resolution. Here, we combined an electroencephalogram (EEG) recording and a temporal response function (TRF) approach to specifically track the neural responses to the foreground and background of a figure texture from the overall EEG recordings in the luminance-tracking TRF. A uniform texture was included as a neutral condition. The texture segregation visual evoked potential (tsVEP) was calculated by subtracting the uniform TRF from the foreground and background TRFs, respectively, to index the specific segregation activity. Results: We found that the foreground and background of a figure texture were processed differently during texture segregation. In the posterior region of the brain, we found a negative component for the foreground tsVEP in the early stage of foreground-background segregation, and two negative components for the background tsVEP in the early and late stages. In the anterior region, we found a positive component for the foreground tsVEP in the late stage, and two positive components for the background tsVEP in the early and late stages of texture processing. Discussion: In this study we investigated the temporal profile of foreground and background processing during texture segregation in human participants at a high time resolution. The results demonstrated that the foreground and background jointly contribute to figure-ground segregation in both the early and late phases of texture processing. Our findings provide novel evidence for the neural correlates of foreground-background modulation during figure-ground segregation in humans.

Model-Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome.

The exposure to ticagrelor (BRILINTA) is higher in the East Asian population compared with the White population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic (PopPK) model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under the concentration-time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning (ML) methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, calcium channel blockers, antidiabetic medications, ß-blockers, peripheral vascular disease, diabetes, transient ischemic attack, sex, and proton pump inhibitor. In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC-AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC-AUC of 0.81. Moreover, the PopPK model and ML algorithm were used to bridge the real-world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.

The Effect of the Mixed Extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai on the Improvement of Degenerative Osteoarthritis through Inflammation Inhibition in the Monosodium Iodoacetate-Induced Mouse Model.

Osteoarthritis is a chronic inflammatory disease, and, due to the lack of fundamental treatment, the main objective is to alleviate pain and prevent cartilage damage. Kalopanax pictus Nakai and Achyranthes japonica Nakai are herbal plants known for their excellent anti-inflammatory properties. The objective of this study is to confirm the potential of a mixture extract of Kalopanax pictus Nakai and Achyranthes japonica Nakai as a functional raw material for improving osteoarthritis through anti-inflammatory effects in macrophages and MIA-induced arthritis experimental animals. In macrophages inflamed by lipopolysaccharide (LPS), treatment of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture inhibits NF-κB and mitogen-activated protein kinase (MAPK) activities, thereby inhibiting inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), inflammatory factors PGE2, MMP-2, and MMP-9, and nitric oxide (NO) was reduced. In addition, in an animal model of arthritis induced by MIA (monosodium iodoacetate), administration of Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture reduced blood levels of inflammatory cytokines TNF-α and IL-6, inflammatory factors prostaglandin E2(PGE2), matrix metalloproteinase-2(MMP-2), and NO. Through these anti-inflammatory effects, MIA-induced pain reduction (recovery of clinical index, increase in weight bearing, and increase in area and width of the foot), recovery of meniscus damage, loss of cartilage tissue or inflammatory cells in tissue infiltration reduction, and recovery of the proteglycan layer were confirmed. Therefore, it is considered that Kalopanax pictus Nakai and Achyranthes japonica Nakai mixture has the potential as a functional raw material that promotes joint health.

Transcriptomic and Functional Analyses of Two Cadmium Hyper-Enriched Duckweed Strains Reveal Putative Cadmium Tolerance Mechanisms.

Cadmium (Cd) is one of the most toxic metals in the environment and exerts deleterious effects on plant growth and production. Duckweed has been reported as a promising candidate for Cd phytoremediation. In this study, the growth, Cd enrichment, and antioxidant enzyme activity of duckweed were investigated. We found that both high-Cd-tolerance duckweed (HCD) and low-Cd-tolerance duckweed (LCD) strains exposed to Cd were hyper-enriched with Cd. To further explore the underlying molecular mechanisms, a genome-wide transcriptome analysis was performed. The results showed that the growth rate, chlorophyll content, and antioxidant enzyme activities of duckweed were significantly affected by Cd stress and differed between the two strains. In the genome-wide transcriptome analysis, the RNA-seq library generated 544,347,670 clean reads, and 1608 and 2045 differentially expressed genes were identified between HCD and LCD, respectively. The antioxidant system was significantly expressed during ribosomal biosynthesis in HCD but not in LCD. Fatty acid metabolism and ethanol production were significantly increased in LCD. Alpha-linolenic acid metabolism likely plays an important role in Cd detoxification in duckweed. These findings contribute to the understanding of Cd tolerance mechanisms in hyperaccumulator plants and lay the foundation for future phytoremediation studies.

Effects of microplastics and cadmium on growth rate, photosynthetic pigment content and antioxidant enzymes of duckweed (Lemma minor).

Cadmium (Cd) and polyethylene (PE) seriously contaminate the aquatic environment and threaten human health. Many studies have reported the toxic effects of Cd and PE on plants, whereas few have reported the combined contamination of these two pollutants. In this study, duckweed (Lemma minor) was used as an indicator to explore the effect of PE microplastics (PE-MPs) at concentrations of 10, 50, 100, 200, and 500 mg/L on tolerance to 1 mg/L Cd. The results showed that different concentrations of PE-MPs inhibited the growth rate and chlorophyll content of duckweed to different degrees, both of which were minimal at 50 mg/L PE-MPs, 0.11 g/d, and 0.32 mg/g, respectively. The highest Cd enrichment (7.77 mg/kg) and bioaccumulation factors (94.22) of duckweed were detected when Cd was co-exposed with 50 mg/L of PE-MPs. Catalase and peroxidase activity first decreased and then increased with increasing PE-MPs concentrations, showing "hormesis effects", with minimum values of 11.47 U/g and 196.00 U/g, respectively. With increasing concentrations of PE-MPs, the effect on superoxide dismutase activity increased and then declined, peaking at 162.05 U/g, and displaying an "inverted V" trend. The amount of malondialdehyde rose with different PE-MPs concentrations. This research lay a foundation for using duckweed to purify water contaminated with MPs and heavy metals.

Efficient and Selective Oxygenation of Cycloalkanes and Alkyl Aromatics with Oxygen through Synergistic Catalysis of Bimetallic Active Centers in Two-Dimensional Metal-Organic Frameworks Based on Metalloporphyrins.

Confined catalytic realms and synergistic catalysis sites were constructed using bimetallic active centers in two-dimensional metal-organic frameworks (MOFs) to achieve highly selective oxygenation of cycloalkanes and alkyl aromatics with oxygen towards partly oxygenated products. Every necessary characterization was carried out for all the two-dimensional MOFs. The selective oxygenation of cycloalkanes and alkyl aromatics with oxygen was accomplished with exceptional catalytic performance using two-dimensional MOF Co-TCPPNi as a catalyst. Employing Co-TCPPNi as a catalyst, both the conversion and selectivity were improved for all the hydrocarbons investigated. Less disordered autoxidation at mild conditions, inhibited free-radical diffusion by confined catalytic realms, and synergistic C-H bond oxygenation catalyzed by second metal center Ni employing oxygenation intermediate R-OOH as oxidant were the factors for the satisfying result of Co-TCPPNi as a catalyst. When homogeneous metalloporphyrin T(4-COOCH3)PPCo was replaced by Co-TCPPNi, the conversion in cyclohexane oxygenation was enhanced from 4.4% to 5.6%, and the selectivity of partly oxygenated products increased from 85.4% to 92.9%. The synergistic catalytic mechanisms were studied using EPR research, and a catalysis model was obtained for the oxygenation of C-H bonds with O2. This research offered a novel and essential reference for both the efficient and selective oxygenation of C-H bonds and other key chemical reactions involving free radicals.

[Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond].

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Anti-tumor effects of novel alkannin derivatives with potent selectivity on comprehensive analysis.

BACKGROUND: Therapeutic approaches based on glycolysis and energy metabolism of tumor cells are new promising strategies for the treatment of cancer. Currently, researches on the inhibition of pyruvate kinase M2, a key rate limiting enzyme in glycolysis, have been corroborated as an effective cancer therapy. Alkannin is a potent pyruvate kinase M2 inhibitor. However, its non-selective cytotoxicity has affected its subsequent clinical application. Thus, it needs to be structurally modified to develop novel derivatives with high selectivity. PURPOSE: Our study aimed to ameliorate the toxicity of alkannin through structural modification and elucidate the mechanism of the superior derivative 23 in lung cancer therapy. METHODS: On the basis of the principle of collocation, different amino acids and oxygen-containing heterocycles were introduced into the hydroxyl group of the alkannin side chain. We examined the cell viability of all derivatives on three tumor cells (HepG2, A549 and HCT116) and two normal cells (L02 and MDCK) by MTT assay. Besides, the effect of derivative 23 on the morphology of A549 cells as observed by Giemsa and DAPI staining, respectively. Flow cytometry was performed to assess the effects of derivative 23 on apoptosis and cell cycle arrest. To further assess the effect of derivative 23 on the Pyruvate kinase M2 in glycolysis, an enzyme activity assay and western blot assay were performed. Finally, in vivo the antitumor activity and safety of the derivative 23 were evaluated by using Lewis mouse lung cancer xenograft model. RESULTS: Twenty-three novel alkannin derivatives were designed and synthesized to improve the cytotoxicity selectivity. Among these derivatives, derivative 23 showed the highest cytotoxicity selectivity between cancer and normal cells. The anti-proliferative activity of derivative 23 on A549 cells (IC50 = 1.67 ± 0.34 µM) was 10-fold higher than L02 cells (IC50 = 16.77 ± 1.44 µM) and 5-fold higher than MDCK cells (IC50 = 9.23 ± 0.29 µM) respectively. Subsequently, fluorescent staining and flow cytometric analysis showed that derivative 23 was able to induce apoptosis of A549 cells and arrest the cell cycle in the G0/G1 phase. In addition, the mechanistic studies suggested derivative 23 was an inhibitor of pyruvate kinase; it could regulate glycolysis by inhibiting the activation of the phosphorylation of PKM2/STAT3 signaling pathway. Furthermore, studies in vivo demonstrated derivative 23 significantly inhibited the growth of xenograft tumor. CONCLUSION: In this study, alkannin selectivity is reported to be significantly improved following structural modification, and derivative 23 is first shown to be able to inhibit lung cancer growth via the PKM2/STAT3 phosphorylation signaling pathway in vitro, indicating the potential value of derivative 23 in treating lung cancer.

Life history responses of the small brown planthopper Laodelphax striatellus to temperature change.

Temperature is a key environmental factor in ectotherms and influences many life history traits. In the present study, the nymphal development time, sex ratio and wing dimorphism of the small brown planthopper Laodelphax striatellus were examined under the conditions of constant temperatures, naturally varying temperatures (or different generations), and different temperatures combined with different photoperiod. The results showed that from 18 to 28 °C, the developmental time of nymphs was gradually shortened with the increase of temperature, whereas the high temperatures of 30 and 32 °C in the third to fifth instar nymphal stages and high summer temperature of 28.8 and 29.7 °C significantly delayed developmental time and resulted in higher mortality of nymphs. In all treatments, the developmental time was longer in females than males. The nymphs took significantly longer time to develop in the short daylength of 12 h than in longer daylengths of 13, 14, 15 and 16. Differences in developmental time were also found between wing morph, with long-winged individuals being significantly longer than the short-winged individuals at lower temperatures and significantly shorter than the short-winged individuals at higher temperatures. In all treatments, the sex ratio was stable, approaching 1:1, without being affected by temperature, generations and photoperiod. Photoperiod and temperature had significantly influence on the wing dimorphism. Long daylength combined with different temperatures resulted in significantly higher proportions of long-winged morph, whereas the low temperatures combined with the short daylengths in autumn and winter resulted in significantly high proportion of short-winged morph. This study broadens our understanding of the life-history traits of this planthopper and provides basic data for analyzing the effects of climate change on the planthopper reproduction.

[Clinical observation on treatment of PC-BPPV by dynamic and static acupuncture method combined with manual reduction].

OBJECTIVE: To observe the clinical effect and advantages of dynamic and static acupuncture method combined with manual reduction on posterior semicircular canal benign paroxysmal positional vertigo (PC-BPPV). METHODS: Ninety patients with PC-BPPV who met the inclusion criteria were randomly divided into manual reduction control group, acupuncture control group and experimental group, with 30 cases in each group. Epley reduction method was used for manual reduction control treatment of patients in the manual reduction control group, until there was no obvious vertigo of patients. Patients in the acupuncture control group received ordinary acupuncture treatment, while patients in the experiment group received dynamic and static acupuncture treatment, both on the basis of manual reduction control treatment. Baihui(GV20) and Yintang(GV24+), Sanyinjiao(SP6), Zhongzhu(TE3), Houxi(SI3) and Waiguan(TE5) on the healthy side, and the vertigo-auditory area and Fengchi(GB20) on the affected side were selected for acupuncture intervention, which was performed once a day, with needles retained for 30 minutes in two acupuncture groups. Every six times was taken as a session and two sessions were required. Dizziness handicap inventory (DHI) scale and visual analogue score (VAS) were used to evaluate the degree of vertigo before, after 1 and 2 sessions of treatment respectively. RESULTS: Compared with those before treatment, the DHI score and VAS score of each group after 1 and 2 sessions of treatment were both significantly decreased (P<0.05). Compared with the acupuncture control group and the manual reduction control group, the DHI score of the experiment group was significantly decreased (P<0.05) after 1 and 2 sessions of treatment. VAS score of the experiment group was significantly decreased compared with that of the manual reduction control group(P<0.05) after 1 and 2 sessions of treatment. The total effective rate of the experiment group was 86.67%, better than those of the acupuncture control group (83.33%, P<0.05) and the manual reduction control group(66.67%, P<0.05). CONCLUSION: The dynamic and static acupuncture method combined with manual reduction effectively improved vertigo symptoms in PC-BPPV with rapid and lasting effects, which is worthy of further clinical promotion and application.

Physiologically Based Pharmacokinetic Model for Older Adults and Its Application in Geriatric Drug Research.

Drug-related adverse events are higher in older patients than in non-older patients, increasing the risk of medication and reducing compliance. Aging is accompanied by a decline in physiological functions and metabolic weakening. Most tissues and organs undergo anatomical and physiological changes that may affect the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of drugs. Clinical trials are the gold standard for selecting appropriate dosing regimens. However, older patients are generally underrepresented in clinical trials, resulting in a lack of evidence for establishing an optimal dosing regimen for older adults. The physiologically based pharmacokinetic (PBPK) model is an effective approach to quantitatively describe the absorption, distribution, metabolism, and excretion of drugs in older adults by integrating physiological parameters, drug physicochemical properties, and preclinical or clinical PK data. The PBPK model can simulate the PK/PD characteristics of clinical drugs in different scenarios, ultimately compensating for inadequate clinical trial data in older adults, and is recommended by the Food and Drug Administration for clinical pharmacology studies in older adults. This review describes the effects of physiological changes on the PK/PD process in older adults and summarises the research progress of PBPK models. Future developments of PBPK models are also discussed, together with the application of PBPK models in older adults, aiming to assist the development of clinical study strategies in older adults.

[Effects of electroacupuncture at "Siguan" points on the expression of colonic 5-hydroxytryptamine and fecal short-chain fatty acids in rats with post-stroke depression].

OBJECTIVE: To observe the effects of electroacupuncture at "Siguan" points on behavior, colonic 5-hydroxytryptamine (5-HT) and fecal short-chain fatty acids (SCFAs) in rats with post-stroke depression (PSD), and explore the effect mechanism of electroacupuncture at Siguan points on PSD. METHODS: Fifty SD rats were randomly divided into a sham-operation group, a stroke group, a PSD group, a drug group and an electroacupuncture group, with 10 rats in each one. The stroke model was established by middle cerebral artery occlusion (MCAO) method in the stroke group; except for the sham-operation group, the rats in the other groups were intervened with MCAO combined with solitary and chronic unpredictable mild stress (CUMS) to establish PSD model. In the electroacupuncture group, electroacupuncture was delivered at "Hegu" (LI 4) and "Taichong" (LR 3), with disperse-dense wave, 2 Hz/10 Hz in frequency, for 30 min in each intervention, once daily, for consecutive 21 days. Simultaneously, distilled water (0.01 L•kg-1•d-1) was administrated intragastrically. Fluoxetine solution (2.33 mg•kg-1•d-1) was given by gavage , once a day and for 21 days in the drug group. The same procedure of fixation and gavage with distilled water were adopted in the sham-operation group, the stroke group and the PSD group. Separately, before stroke modeling, after PSD modeling and after 21-day intervention, the consumption of sugar water and the scores of horizontal movement and vertical movement in open-field test were observed. After 21-day intervention, the content of colonic 5-HT was detected by immunohistochemical method, and that of fecal SCFAs was determined by gas chromatography mass spectrometry. RESULTS: After PSD modeling, compared with the stroke group, the sugar water consumption, the horizontal movement scores and vertical movement scores of the open-field test were all reduced in the PSD group, the drug group and the electroacupuncture group (P<0.05). After 21-day intervention, the sugar water consumption and the scores of horizontal movement and vertical movement of the open-field test were increased in the drug group and the electroacupuncture group (P<0.05) when compared with the PSD group; and the horizontal movement score in the electroacupuncture group was lower than that of the drug group (P<0.05). Compared with the sham-operation group, the contents of total fecal SCFAs and acetic acid were lower in the stroke group (P<0.05), and the contents of colonic 5-HT and total fecal SCFAs, acetic acid, propionic acid and butyric acid were reduced in the PSD group (P<0.05). In comparison with the PSD group, the contents of colonic 5-HT and total fecal SCFAs, acetic acid and propionic acid were increased in the drug group and the electroacupuncture group (P<0.05); and the content of colonic 5-HT in the electroacupuncture group was lower than that of the drug group (P<0.05). The level of colonic 5-HT was positively correlated with the contents of total fecal SCFAs and propionic acid (r=0.424, P=0.005; r=0.427, P=0.004). CONCLUSION: Electroacupuncture at "Siguan" points can relieve the depression-like behavior of PSD rats, and its underlying mechanism may be related to the regulation of fecal SCFAs, which affects the release of colonic 5-HT.